Prenatal immune activation and adult Poly(I:C) re-challenge promote neuroimmune priming and AD-related behavioural, cellular and molecular alterations in wild-type mice.

内容摘要

Alzheimer's Disease (AD) is neurodegenerative disorder characterized by deposition of Aβ plaques, tau-positive neurofibrillary tangles, neuroinflammation and clinical dementia. Epidemiological and experimental evidence suggest that peripheral immune inflammation is a risk factor for age-related neurodegeneration but whether its sustained activation is sufficient to drive behavioural, molecular and cellular changes consistent with AD-associated neurodegenerative vulnerability remains unclear. Here we investigated whether prenatal immune stimulation followed by an adult systemic re-challenge with Polyinosinic-polycytidylic acid (Poly(I:C)) induces persistent cognitive/motivational/social deficits and hippocampal neurodegeneration in wild-type mice, consistent with long-lasting neuroimmune priming mechanism(s). Pregnant C57Bl/6J dams received intravenously Poly(I:C) at gestational day 17 and male offspring received intraperitoneal Poly(I:C) at 9 months (single- or double-hit design) and were analyzed at 12 months. Recognition memory, working memory, reward-related learning, and social interaction were assessed followed by hippocampal Western blotting and immunofluorescence. Poly(I:C)-exposed mice exhibited impaired recognition and working memory, reduced palatable food-induced conditioned place preference, and blunted social investigation. These behavioral abnormalities were accompanied by increased amyloidogenic APP processing (BACE1/PSEN1 upregulation and β-CTF accumulation), tau dysregulation (AT8 hyperphosphorylation), microglial activation (Iba1/CD68 upregulation and process retraction), synaptic alterations (α-synuclein reduction), and bioenergetic impairment (reduced mitochondrial and glycolytic markers) in the hippocampus. Overall, these findings indicate that repeated prenatal and postnatal peripheral activation of innate immunity may act as a contributing factor to neurodegenerative phenotype with features relevant to AD-related susceptibility, paving the way for the development of next-generation therapeutical interventions affecting systemic-to-brain inflammatory signaling.